Quinolone carboxylic acid derivatives and process for preparing the same

ABSTRACT

The present invention relates to quinolone carboxylic acid derivatives having useful antibacterial activities of formula (I): ##STR1## wherein, R 1 , R 2 , and R 3 , which may be the same or different, are each hydrogen or a halogen atom, or a lower alkyl group optionally substituted with an amino or a hydroxy group; 
     R 4  is hydrogen atom, a lower alkyl, benzyl, t-butoxycarbonyl or ethoxycarbonyl group; 
     R 5  is hydrogen, chlorine atom, methyl or an amino group; 
     R 6  is a lower alkyl group, or a cyclopropyl or a phenyl group optionally substituted with a halogen atom; and 
     X is nitrogen atom, or a methyne group optionally substituted with a lower alkyl or a lower alkoxy group or a halogen atom, and pharmaceutically acceptable salts thereof, and processes for preparing these compounds. The present invention also relates to novel intermediates which are useful for preparing the quinolone compounds of the invention.

CROSS REFERENCE

This application is a division of application Ser. No. 08/277,602, filed on Jul. 20, 1994, now allowed, which in turn is a continuation-in-part of application Ser. No. 08/052,711, filed Apr. 26, 1993, now abandoned.

FIELD OF THE INVENTION

The present invention relates to novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof which possess a broad spectrum of potent antibacterial activities and are useful as antibacterials and to processes for preparing these compounds.

DESCRIPTION OF THE PRIOR ART

Quinolone carboxylic acid-type antibacterials are known to exhibit strong antibacterial activity against aerobic Gram-negative bacteria. Among these quinolone carboxylic acid-type antibacterials, especially enoxacin, norfloxacin, ofloxacin, ciprofloxacin and tosufloxacin are clinically used. However, these prior art quinolones are known to have relatively weak activity against Gram-positive bacteria, while they have superior antibacterial activity against Gram-negative bacteria.

Therefore, the development of new quinolone carboxylic acid-type compounds which possess a broad spectrum of antibacterial activities and are effective against quinolone-resistant bacteria as well as methicillin-resistant Staphylococcus aureus (MRSA) is still needed.

SUMMARY OF THE INVENTION

In order to solve the above problems, the present inventors have conducted extensive studies to develop novel quionlone compounds.

As a result, it has been surprisingly found that quinolone carboxylic acid derivatives having the substituent represented by the following formula (A) at 7-position of quinolone nucleus meet the above requirements. ##STR2## In the above formula, R₁, R₂ and R₃, which may be the same or different, are each hydrogen or a halogen atom, or a lower alkyl group optionally substituted with an amino or hydroxy group; and

R₄ is hydrogen atom, a lower alkyl, benzyl, t-butoxycarbonyl or ethoxycarbonyl group.

Accordingly, the present invention is concerned with novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof which can meet said requirements and with processes for preparing such compounds.

DETAILED DESCRIPTION OF THE INVENTION

An object of the present invention is to provide novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof which possess a broad spectrum of antibacterial activities against various microorganisms, and to provide processes for preparing these compounds.

Another object of the present invention is to provide intermediates which are useful for producing the desired compounds of the present invention.

The present invention provides novel quinolone carboxylic acid derivatives represented by the formula (I): ##STR3## wherein, R₁, R₂, R₃ and R₄ are the same as defined above;

R₅ is hydrogen or chlorine atom, or methyl or an amino group;

R₆ is a lower alkyl group, or a cyclopropyl or a phenyl group optionally substituted with a halogen atom; and

X is nitrogen atom, or a methyne group optionally substituted with a lower alkyl or a lower alkoxy group or a halogen atom, and their pharmaceutically acceptable salts.

The term "lower alkyl" used herein refers to a straight or branched C₁₋₄ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

The term "halogen atom" used herein refers to a chlorine, bromine, fluorine or iodine atom.

The term "lower alkoxy" used herein refers to C₁₋₄ alkoxy such as methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, sec-butyloxy or tert-butyloxy.

Among the compounds of the present invention, the preferred compounds which possess a broad spectrum of antibacterial activities are as follows:

1-cyclopropyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinolone-4-oxo-3-carboxylic acid;

1-cyclopropyl-6-fluoro-8-chloro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinolline-4-oxo-3-carboxylic acid;

1-(2-fluorocyclopropyl)-6-fluoro-8-chloro-7-[(2.8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1-cyclopropyl-5,8-dichloro-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5- en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1-cyclopropyl-5-amino-6,8-difluoro-7-[2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1-cyclopropyl-6,8-dichloro-7-[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1-(2-fluorocyclopropyl)-5,8-dichloro-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid; and

1-cyclopropyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid.

Among the compounds of the present invention, the more preferred compounds which possess a broad spectrum of antibacterial activities are as follows:

1-cyclopropyl-6,8-difluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1-cyclopropyl-6-fluoro-8-chloro-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1- cyclopropyl-5,8-dichloro-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1-cyclopropyl-5-amino-6,8-difluoro-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid;

1-(2-fluorocyclopropyl)-6-fluoro-8-chloro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid; and

1-cyclopropyl-6-fluoro-8-methoxy-7[-(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid.

Quinolone compounds represented by formula (I) according to the present invention can be prepared by either process (A) or (B) set forth hereinafter. ##STR4## In the above formula,

R₁, R₂, R₃, R₄, R₅, R₆ and X are the same as defined previously; and Y is a halogen atom or a mesyl or a tosyl group.

In accordance with the above process (A), quinoline compounds represented by formula (I) of the present invention can be prepared by reacting a compound of formula (II) with a compound of formula (III) in a solvent, preferably in the presence of an inorganic or organic base. Solvents used in this process include water, a lower alkanol, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide and a mixture thereof. Inorganic bases used herein include calcium carbonate, potassium carbonate and the like. Organic bases used herein include 1,8-diazabicyclo[5.4.0-undec-7-ene(DBU), triethylamine and the like. The above reaction may be carried out at a temperature between about 20° and about 200° C., preferably between about 60° and about 130° C. The reaction time is about 1 to about 24 hours. ##STR5## In the above formula,

R₁, R₂, R₃, R₄, R₅, R₆, X and Y are the same as defined above; and R is hydrogen atom or a lower alkyl group.

The above Process (B) comprises the following four steps;

Step (1):

The compound of formula (V) can be prepared by reacting a compound of formula (IV) with a compound of formula (II). The above reaction can be conducted in the presence of a solvent such as a lower alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydroxide and sodium carbonate or an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine at a temperature ranging from about 0° C. to the refulx temperature of the solvent employed.

Step (2):

The compound of formula (VII) can be obtained by condensing with an amine compound of formula (VI) after a compound of formula (V) is heated under reflux with ethyl orthoformate and acetic anhydride. The condensation reaction is preferably carried out with a solvent such as ethanol, dimethylsulfoxide, acetone, 1,4-dioxane or a mixture thereof at a temperature ranging from 0° to 50° C.

Step (3):

The compound of formula (VIII) can be obtained by cyclizing a compound of formula (VII); and said cyclization reaction is preferably carried out by employing a reaction solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture thereof, preferably in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium fluoride and potassium fluoride or an organic base such as triethylamine and pyridine at a temperature ranging from 0° C. to the reflux temperature of the solvent employed.

Step (4):

The compound of formula (I) can be prepared by hydrolyzing a compound of formula (VIII) obtained from Step (3) above. The hydrolysis can be carried out by employing a conventional method such as acid or base treatment.

The intermediates obtained in process(B), i.e., the respective compounds of formula (V), (VII) and (VIII) are novel compounds; and therefore, the present invention also includes these compounds.

The compounds employed as starting materials in accordance with the present invention are commercially available and also can be obtained through known processes in the art.

For example, one of the compounds of formula (III) can be prepared by the following process (I) described in J. Med. Chem. 31, 503 (1988). ##STR6##

a: (COCl)₂, H₂ CCl₂, DMF, b: malonic monoester dianion; c: HC(OEt)₃, Ac₂ O; d: c-C₃ H₅ --NH₂ ; e: t-BuOK, t-BuOH; f: RaNi; g: HCl.

The 6-nitro-2,3,4,5-tetrafluorobenzoic acid was converted to the keto ester with dianion of malonic half ester (step 1) and finally to 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid by the general route reported by Chu, D. T. J. Heterocycl. Chem. 22, 1033 (1985).

Another compound of formula (III) can be prepared by the following process (II) described in Drugs of the Future, 14, 931 (1989). ##STR7##

The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (i) with Fe-HCI in hot water gives 2,3,4-trichloro-5-fluoroaniline (ii), which, by diazotization with NaNO₂ -HCI and reaction with sodium tetra-fluoroborate and cuprous cyanide, is converted to 2,3,4-trichloro-5-fluorobenzonitrile (iii). The reaction of (iii) with KF in DMSO at 140° affords 3-chloro-2,4,5-trifluorobenzonitrile (iv), which, by hydrolysis with 30% HBr in refluxing acetic acid, gives 3-chloro-2,4,5-trifluorobenzamide (v). The hydrolysis of (v) with 18N H₂ SO₄ at 135° yields the corresponding benzoic acid (vi), which is treated with refluxing SOCl₂ to afford the acyl chloride (vii). The condensation of (vii) with diethyl malonate (viii) by means of Mg-ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (ix), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (x). The condensation of (x) with triethyl orthoformate (xi) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (xii), which is treated with cyclopropylamine (xiii) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (xiv). The cyclization of (xiv) by means of NaF in DMF at 150° gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (xv), which is hydrolyzed with H₂ SO₄ in refluxing water-acetic acid to the corresponding carboxylic acid (xvi).

One of the compounds of formula (IV) can be prepared by the condensation of ethyl ethoxymagnesium malonate with 2,3,4,5-tetrafluorobenzoyl chloride (accessible from the corresponding carboxylic acids), followed by hydrolysis of the condensate [Chem. Pharm. Bull. 34(10) 4098 (1986)].

The compound of formula (I) can be converted into their pharmaceutically acceptable salts by employing conventional methods. For example, the compound of formula (I) can be converted into the salt with an inorganic acid such as hydrochloric, sulfuric and phosphoric acids, or an organic acid such as methanesulfonic, lactic, oxalic and acetic acids, or a salt of an alkaline metal such as sodium and potassium.

The most preferred compounds according to the present invention are optical isomers of the compounds represented by formula (I). These optical isomers according to formula (I) are represented by Formula (IA) or Formula (IA') and their pharmaceutically acceptable salts. ##STR8## In the above formulae, A represent nitrogen or ##STR9## in which Y represents hydrogen, halogen such as fluorine or chlorine, lower alkyl or lower alkoxy such as methoxy, or together with R₁ forms --CH₂ CH₂ CH₂ --, --CH₂ CH₂ CH(CH₋)--, --OCH₂ CH₂ --, --OCH₂ CH(CH₃)--, SCH₂ CH₂ -- or --SCH₂ CH(CH₃)--;

R₁ is as defined above or represents a straight chain alkyl group having 1 to 3 carbon atoms which is optionally substituted with a halogen atom or a cyclopropyl group which is optionally substituted with a halogen atom, a phenyl group, or a phenyl group substituted with one or two halogen atoms, such as ethyl, cyclopropyl or 2,4-difluorophenyl;

R₄ represents hydrogen, lower alkyl, lower alkoxy, or an amino-protecting group, such as methyl, ethyl or butoxycarbonyl;

R₅, R₆, R₇ and R₈ may be the same or different and represent independently hydrogen, lower alkyl optionally substituted by amino, hydroxy or halogen, such as methyl or ethyl; and

X represents hydrogen, halogen such as fluorine or chlorine, amino or lower alkyl such as methyl.

Lower alkyl is preferably C₁₋₆ alkyl, more preferably C₁₋₄, such as methyl or ethyl.

The compounds according to Formulas (IA) and (IA') are formed according to process A or B described above using compounds according to Formula (IIa) or (IIa'): ##STR10## wherein R₄, R₅, R₆, R₇ and R₈ are the same as defined above, and B is hydrogen, lower alkyl, lower alkoxy, or an amino-protecting group, such as methyl, ethyl or butoxycarbonyl.

Preferred compounds of Formula (IA) or (IA') of the present invention which show strong antibacterial activity and posses a broad antibacterial spectrum are:

1-cyclopropyl-6-fluoro-7-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid;

1-cyclopropyl-6-fluoro-7-(((-)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl)-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid;

1-cyclopropyl-6-fluoro-7-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl)-8-chloro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid;

1-cyclopropyl-5-amino-6,8-difluoro-7-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid;

9-fluoro-3-(S)-methyl-10-((+)-2,8-diazabicyclo[4.3.0]non-5-en-8-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-[1,4]-benzoxazin-6-carboxylic acid; and pharmaceutically acceptable salts thereof.

Compounds of Formula (IIa) and (IIa') of the present invention may be prepared by the process illustrated below. ##STR11## In the above formulae, R₅, R₆, R₇ and R₈ are the same as defined above, and R represents amine-protecting group such as toluenesulfonyl or t-butoxycarbonyl.

Preferred compounds of Formula (IIa) or (IIa') of the present invention are:

(+)-2,8-diazabicyclo[4.3.0]non-5-ene; and

(-)-2,8-diazabicyclo[4.3.0]non-5-ene.

Compound (II) is reacted with N-tosyl-L-prolyl chloride in an organic solvent such as methylene chloride or chloroform or in a mixture of water and the said organic solvents in the presence of an organic base such as triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or an inorganic base such as sodium bicarbonate or sodium carbonate at -20° C. to 30° C. to give Compound (a). Compound (a) may also be prepared by reacting Compound (II) with N-protected L-proline in a solvent such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile or chloroform in the presence of an organic or inorganic base such as triethylamine, DBU or DBN and dicyclokexyl carbodiimide. Compound (a) is subjected to column chromatography and acid-catalized hydrolysis to obtain Compound (IIa) and Compound (IIa').

The following examples are intended to further illustrate the present invention, without limiting the scope of the invention.

EXAMPLE 1 Preparation of 1-cyclopropyl-6,8-difluoro-7-[(2,8 diazabicyclo[4.3.0.]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.43 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.96 g of 2,8-diazabicyclo[4.3.0.]non-5-ene dihydrochloride were suspended in 10 ml of acetonitrile and then 3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene was added thereto. The resulting mixture was heated at 60° C. for 4 hours, and then cooled to room temperature. The resulting white solid was filtered, washed twice with chilled acetonitrile, and then dried to obtain 1.8 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.10(1H, m), 2.30(1H, m), 2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.85(1H, m), 4.00(3H, m), 5.66(1H, m), 7.80(1H, d), 8.65(1H, s)

EXAMPLE 2 Preparation of 1-cyclopropyl-6-fluoro-8-chloro-7[2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.50 g of 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.97 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were dissolved in 10 ml of dimethylformamide, and then 4 ml of pyridine was added thereto. The reaction mixture was heated at 100° C. for 6 hours. The reaction solvent was removed under reduced pressure at below 40° C. and the residue was washed with water, then with chilled acetonitrile, and dried to obtain 1.2 g of the desired compound as a white solid.

¹ H-NMR(CDCl₃, δ): 1.20(4H, m), 2.10(1H, m), 2.30(1H, m), 2.65˜4.15(7H, m), 4.95(1H, m), 5.10(1H, m), 5.60(1H, m), 7.56(1H, d), 8.61(1H, s)

EXAMPLE 3 Preparation of 1-cyclopropyl-6-fluoro-8-methoxy-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.47 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.97 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.31 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.16(4H, m), 2.11(1H, m), 2.70˜4.15(7H, m), 4.02(3H, s), 4.65(1H, d), 5.70(1H, s), 7.84(1H, d), 8.80(1H, s)

EXAMPLE 4 Preparation of 1-cyclopropyl-6-fluoro-7-[2,8-diazobicyclo [4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3carboxylic acid

1.32 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.97 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.56 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.23(1H, m), 2.32(1H, m), 2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.81(1H, m), 4.0(3H, m), 4.65(1H, d), 5.75(1H, s), 6.99(1H, d), 7.82(1H, d), 8.62(1H, s)

EXAMPLE 5 Preparation of 1-cyclopropyl-6-fluoro-8-methyl-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.40 g of 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.97 g of 2,8-diazabicyclo[4.3.0]-non-5-ene dihydrochloride were suspended in 15 ml of acetonitrile, and then 4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene was added thereto. The resulting mixture was heated under reflux for 10 hours. The reaction solvent was evaporated under reduced pressure, and the residue was suspended in water, stirred and filtered. The resulting solid was treated with aqueous sodium bicarbonate solution to dissolve the solid, and then adjusted to pH 2 with 10% hydrochloric acid to obtain the pure solid product. The resulting solid was filtered, and then evaporated under reduced pressure to obtain 0.87 g of the desired compound as a white solid.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.10(1H, m), 2.3(3H, s), 2.70˜4.16(7H, m), 4.95(1H, m), 5.10(1H, m), 5.62(1H, m), 7.61(1H, d), 8.61(1H, s)

EXAMPLE 6 Preparation of 1-cyclopropyl-5-amino-6,8-difluoro-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.50 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.98 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.60 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H), 2.12(1H, m), 2.30(1H, m), 2.95(1H, m), 3.25˜4.0(6H, m), 4.65(1H, d), 5.75(1H, s), 8.92(1H, s)

EXAMPLE 7 Preparation of 1-cyclopropyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0.]non-5-en)-8-yl]-oxo-1,8-naphthyridine-3-carboxylic acid

1.41 g of 1-cyclopropyl-6,7-difluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 0.97 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.87 g of the desired compound.

¹ H-NMR(CDCl₃ +d₆ -DMSO, δ): 1.15(4H, m), 2.23(1H, m), 2.32(1H, m), 2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.81(1H, m), 4.0(3H, m), 4.65(1H, d), 5.75(1H, s), 7.99(1H, d), 8.71(1H, s)

EXAMPLE 8 Preparation of 1-ethyl-6-fluoro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.26 g of 1-ethyl-6,7-difluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 9.80 g of 2,8diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.43 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.26(3H, t), 2.12(1H, m), 2.30˜4.15(10H, m), 4.95(1H, m), 4.0(2H, m), 5.10(1H, m), 5.60(1H, m), 7.01(1H, d), 7.51(1H, d), 8.68(1H, s)

EXAMPLE 9 Preparation of 1-(2,4-difluorophenyl)-6-fluoro-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-1,8-naphthyridine-3-carboxylic acid

1.20 g of 1-(2,4)-difluorophenyl)-6,7-difluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 0.65 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 2 to obtain 1.31 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.17(4H, m), 2.12(1H, m), 2.29(1H, m), 2.36(1H, m), 3.25(1H, m), 3.60(1H, m), 3.39(1H, m), 4.0(3H, m), 4.71(1H, d), 5.75(1H, s), 7.45(1H, m), 7.73(1H, m), 7.94(1H, m), 7.95(1H, d), 8.80(1H, s)

EXAMPLE 10 Preparation of 1-cyclopropyl-6,8-difluoro-7-[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.42 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.05 g of subjected to the same process as described in Example 1 to obtain 1.96 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.10˜4.15(12H, m), 4.95(1H, m), 5.10(1H, m), 7.78(1H, d), 8.71(1H, s)

EXAMPLE 11 Preparation of 1-cyclopropyl-6-fluoro-8-chloro-7-[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.50 g of 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.96 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.08(4H, m), 2.10˜2.30(5H, m), 2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.85(1H, m), 4.0(3H, m), 4.65(1H, d), 7.54(1H, d), 8.64(1H, s)

EXAMPLE 12 Preparation of 1-cyclopropyl-6-fluoro-8-methoxy-7[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.48 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 2.16 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.11(1H, m), 2.30(1H, m), 2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.85(1H, m), 4.0(3H, m), 4.10(3H, s), 4.65(1H, d), 7.86(1H, d), 8.84(1H, s)

EXAMPLE 13 Preparation of 1-cyclopropyl-5-amino-6,8-difluoro-7-[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.50 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 2.06 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.12˜2.30(5H, m), 2.95(1H, m), 3.25˜4.0(6H, m), 4.68(1H, d), 8.94(1H, s)

EXAMPLE 14 Preparation of 1-cyclopropyl-6-fluoro-7-[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,8-dihydronaphthyridine-3-carboxylic acid

1.41 g of 1-cyclopropyl-6-fluoro-7-chloro-1,8-dihydronaphthyridine-3-carboxylic acid and 1.04 g of 2-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.91 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.12˜2.30(5H, m), 2.95(1H, m), 3.25˜4.0(6H, m), 4.68(1H, d), 7.85(1H, d), 8.68(1H, s)

EXAMPLE 15 Preparation of 1-cyclopropyl-6,8-difluoro-7-[(3-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.41 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 3-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 2.20 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15˜1.27(7H, m), 2.16˜2.36(2H, m), 2.95(1H, m), 3.25˜4.10(6H, m), 5.52(1H, m), 7.78(1H, d), 8.76(1H, s)

EXAMPLE 16 Preparation of 1-cyclopropyl-6-fluoro-8-chloro-7[(3-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.50 g of 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 3-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.83 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.16˜1.22(4H, m), 2.08˜4.16(9H, m), 4.95(1H, m), 5.49(1H, m), 7.81(1H, d), 8.78(1H, s)

EXAMPLE 17 Preparation of 1-cyclopropyl-6-fluoro-8-methoxy-7[(2-methyl -2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.48 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 3-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.91 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.16˜1.25(4H, m), 2.10˜4.16(9H, m), 4.05(3H, s), 4.95(1H, m), 5.49(1H, m), 7.89(1H, d), 8.81(1H, s)

EXAMPLE 18 Preparation of 1-cyclopropyl-5-amino-6,8-difluoro-7-[3-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl[-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.50 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 3-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the sampe process as described in Example 1 to obtain 1.68 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.14˜1.21(7H, m), 2.10˜4.10(9H, m), 4.95(1H, m), 5.56(1H, m), 8.76(1H, s)

EXAMPLE 19 Preparation of 1-cyclopropyl-6,8-difluoro-7[(5-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-dihydroquinoline-4-oxo-3-carboxylic acid

1.42 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 5-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.69 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.23˜2.35(5H, m), 2.95(1H, m), 3.25(1H, m), 3.60(1H, m), 3.81(1H, m), 4.0(3H, m), 4.65(1H, d), 5.75(1H, s), 7.80(1H, d), 8.71(1H, s)

EXAMPLE 20 Preparation of 1-cyclopropyl-6-fluoro-8-chloro-7-[(5-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.50 g of 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 5-methyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the sampe process as described in Example 1 to obtain 1.87 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.14(4H, m), 2.10˜4.12(12H, m), 4.95(1H, m), 5.10(1H, m), 5.62(1H, m), 7.81(1H, d), 8.81(1H, s)

EXAMPLE 21 Preparation of 1-cyclopropyl-6,8-difluoro-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid hydrochloride

0.33 g of 1-cyclopropyl-6,8-difluoro-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid obtained from Example 1 was dissolved in methanol saturated with hydrogen chloride, and the reaction solution was stirred for 1 hour. The resulting solid was filtered, washed with chilled methanol, and then dried to obtain 0.403 g of the desired compound as a light yellow solid.

¹ H-NMR(d₆ -DMSO, δ): 1.16(4H, m), 2.21˜4.06(9H, m), 4.65(1H, d), 5.75(1H, s), 7.81(1H, d), 8.81(1H, s)

EXAMPLE 22 Preparation of 1-cyclopropyl-6-fluoro-8-chloro-7-[(2,8-diazabicylo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid lactate

0.404 g of 1-cyclopropyl-6-fluoro-8-chloro-7-[(2,8-diazabicyclo[4.3.0]non-5-en-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid obtained from Example 2 was dissolved in 5 ml of mixture of chloroform-methanol(5:1, v/v), and then 0.09 g of lactic acid was added thereto. The resulting reaction solution was stirred for 4 hours, evaporated under reduced pressure, washed twice with acetonitrile, and then dried under reduced pressure to obtain 0.40 g of the desired compound.

¹ H-NMR(CD₃ OD, δ): 1.14(1H, m), 2.20˜4.06(11H, m), 4.65(1H, d), 5.75(1H, s), 7.81(1H, d), 8.81(1H, s)

EXAMPLE 23 Preparation of 1-cyclopropyl-6-fluoro-8-methoxy-7-[(5-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid Step (1) Preparation of ethyl{2,5-difluoro-3-methoxy-4-[(5-methyl-2,8-diazabicylo[4.3.0]non-5-en)-8-yl}benzoyl acetate

1.06 g of ethyl(2,4,5-trifluoro-3-methoxy)benzoyl acetate, 0.91 g of 5-methyl-2,8-diazabicyclo[4.3.0]non-5-ene and 1 g of calcium carbonate were added to 10 ml of acetonitrile and the resulting solution was heated at 60° C. for 6 hours. The solvent was evaporated under reduced pressure and the residue was suspended in ethyl acetate, and then washed with water. The solvent was evaporated again under reduced pressure. The residue was purified on a silica gel column chromatography using hexane:ethyl acetate (3:1, v/v) to obtain 1.36 g of the desired compoumnd.

Steps (2) and (3) Preparation of 1-cyclopropyl-6-fluoro-8-methoxy-7-[(5-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid ethyl ester

1.16 g of benzoyl acetate obtained from the above step (1) was dissolved in 10 ml of acetic anhydride, and then 2 g of triethyl carbonate was added thereto. The resulting mixture was heated for 1 hour. After being cooled to room temperature the reaction mixture was poured into 100 ml of ice water. The reaction product was extracted with ethyl acetate, dried over magnesium sulfate, and then evaporated under reduced pressure. The residue was dissolved in ethanol, and 0.51 g of cyclopropylamine was added thereto, and then stirred at room temperature for 3 hours. The reaction mixture was then evaporated under reduced pressure, and the residue was dissolved in 5 ml of dimethylsulfoxide. 3 g of calcium fluoride was added to the resulting solution, and then heated at 60° C. for 1 hour. The reaction mixture was poured into 50 ml of ice water and the reaction product was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then evaporated under reduced pressure. The resulting residue was purified on a silica gel column chromatography using hexane:ethyl acetate(5:1, v/v) to obtain 0.78 g of the desired compound.

Step (4) Preparation of 1-cyclopropyl-6-fluoro-8-methoxy-7-[(5-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

0.71 g of the ester derivative obtained from the above steps (2) and (3) was suspended in 10 ml of 6N hydrochloric acid, and then heated under reflux for 8 hours. The solvent was evaporated under reduced pressure, and the residue was treated with an queous saturated sodium carbonate solution to remove the insoluble material. The resulting solution was washed twice with ethyl acetate, adjusted to pH 3 with 2N hydrochloric acid, and then cooled in an ice water bath to produce white solid which was filtered and then dried under reduced pressure to obtain 0.46 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.16(4H, m), 2.11(1H, m), 2.70˜4.16(10H, m), 4.02(3H, s), 4.65(1H, d), 5.70(1H, d), 7.84(1H, d), 8.80(1H, s)

EXAMPLE 24 Preparation of 1-cyclopropyl-5-methyl-6-fluoro-7[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3carboxylic acid

1.39 g of 1-cyclopropyl-5-methyl-6,7-difluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.04 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.67 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.14(4H, m), 2.10˜2.30(5H, m), 2.65˜4.15(7H, m), 4.95(1H, m), 5.60(1H, m), 7.71(1H, d), 8.69(1H, s)

EXAMPLE 25 Preparation of 1-cyclopropyl-6,8-difluoro-7-](3-hydroxymethyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.43 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.13 g of 3-hydroxymethyl-2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.38 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.10˜2.31(2H, m), 2.76˜3.25(5H, m), 4.0(3H, m), 5.62(1H, m), 7.82(1H, d), 8.67(1H, s)

EXAMPLE 26 Preparation of 1-cyclopropyl-6,8-difluoro-7[(3-aminomethyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.43 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.20 g of 3-aminomethyl-2,8-diazabicyclo [4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.52 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.14(4H, m), 2.14˜2.31(2H, m), 2.76˜3.18(7H, m), 4.0(1H, m), 5.61(1H, m), 7.80(1H, d), 8.71(1H, s)

EXAMPLE 27 Preparation of 1-cyclopropyl-5-amino-7-[(5-fluoro-2,8-diazabicyclo[4.3.0]non-5-en])-8-yl]-6,8-difluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.49 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 1.06 g of 5-fluoro-2,8-diazabicyclo [4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.87 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.14(4H, m), 2.10˜2.30(2H, m), 2.95˜3.25(4H, m), 3.90˜4.00(4H, m), 8.71(1H, s)

EXAMPLE 28 Preparation of 1-cyclopropyl-5,8-dichloro-6-fluoro-7-[(2,8-diazabicyclo [4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.67 g of 1-cyclopropyl-5,8-dichloro-6,7-difluoro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.98 g of 2,8-diazabicyclo [4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.42 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.10(1H, m), 2.30(1H, m), 2.91˜3.25(4H, m), 3.90(1H, m), 4.00()3H, m), 5.60(1H, m), 8.65(1H, s)

EXAMPLE 29 Preparation of 1-(2-fluorocyclopropyl)-6-fluoro-8-chloro-7-[(2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,4-dihydroquinoline-4-oxo-3-carboxylic acid

1.58 g of 1-(2-fluorocyclopropyl)-6,7-difluoro-8-chloro-1,4-dihydroquinoline-4-oxo-3-carboxylic acid and 0.98 g of 2,8-diazabicylo[4.3.0]non-5-ene dihydrochloride were subjected to the same process as described in Example 1 to obtain 1.21 g of the desired compound.

¹ H-NMR(CDCl₃, δ): 1.18(2H, m), 2.12(1H, m), 2.30(1H, m), 2.95(1H, m), 3.25(1H, m), 3.90˜4.00(7H, m), 5.62(1H, m), 8.72(1H, s)

1) Preparation of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride (1) Preparation of 1-benzyl-3-carboethoxy-4-benzylaminopyrrolidine

24.7 g of 1-benzyl-3-carboethoxy-4-pyrrolidone and 10.7 g of benzylamine were added to 100 ml of benzene, and then dehydrated with Dean-Stark distillation apparatus. The residual benzene was evaporated. The residue was dissolved in 200 ml of tetrahydrofuran, and then a small amount of methyl orange was added. To this was added methanol saturated with hydrogen chloride to adjust the pH to about 4, and then 7 g of sodium cyanoborohydride was added thereto. A solution of methanol saturated with hydrogen chloride was added dropwise to the reaction solution with stirring until the pink-color of the solution did not disappear. The reaction solution was basified with 15% aqueous caustic soda solution, and then the reaction mixture was diluted with ether, after which the aqueous layer was separated the aqueous layer was removed by addition of ether. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and then subjected to silica gel column chromatography (hexane:ethyl acetate, 5:1(v/v)) to obtain 24 g of the desired compound (yield: 71%).

¹ H-NMR(CDCl₃, δ): 1.27(3H, t), 2.6˜3.0(5H, m), 3.57(1H, m), 3.63(2H, d), 3.80(2H, s), 4.18(2H, q), 7.31(10H, m)

(2) Preparation of N,N'-dibenzyl-2,8-diazabicyclo[4.3.0]non-5-one

33.8 g of 1-benzyl-3-carboethoxy-4-benzylaminopyrrolidine and 50 ml of ethyl acrylate were added to 100 ml of ethanol, and then refluxed with stirring for 3 days. The ethanol and ethyl acrylate were removed under reduced pressure. The residue was dissolved in 100 ml of toluene, and then the reaction mixture was cooled in an ice water bath. 8 g of potassium t-butoxide was added thereto, and then stirred at room temperature over night. 100 ml of water was added to the reaction mixture, and then stirred well. The aqueous layer was separated, and then neutralized with concentrated sulfuric acid. The aqueous layer was extracted three times with ethyl acetate, and the solvent was then evaporated under reduced pressure. To the residue was added 100 ml of concentrated hydrochloric acid, and the resulting solution was stirred under reflux for 4 hours. The reaction solution was concentrated to a volume of 50 ml under reduced pressure, neutralized with 1N NaOH solution, extracted twice with ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then purified on a silica gel column chromatography (hexane:ethyl acetate, 3:1(v/v) to obtain 17.1 g of the desired compound (yield: 53.4%).

¹ H-NMR(CDCl₃, δ): 2.3˜3.0(9H, m), 3.20˜3.70(2H, ABq), 3.50(2H, s), 3.40(1H, q), 7.15(10H, m)

(3) Preparation of N,N'-dibenzyl-2,8-diazabicyclo[4.3.0]non-5-ol

To a suspension of 4.0 g of NaBH₄ in 100 ml of ethanol was added dropwise a solution of 32.0 g of N,N'-dibenzyl-2,8-diazabicyclo[4.3.0]non-5-one in 100 ml of ethanol. After the reaction mixture was stirred at room temperature for 3 hours, 20 ml of 15% NaOH was added thereto, and then filtered. The filtrate was evaporated under reduced pressure, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to obtain the desired compound in a quantitative yield as a light yellow syrup.

¹ H-NMR(CDCl₃, δ): 1.60˜3.00(11H, m), 3.20˜3.60(3H, m), 3.70(2H, d), 3.90(1H, m), 7.30(10H, m)

(4) Preparation of N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ol

32.2 g of N,N'-dibenzyl-2,8-diazabicyclo[4.3.0]non-5-ol was added to 250 ml of methanol containing 10 ml of formic acid together with 3 g of 10% Pd/C, then agitated under hydrogen gas (initial pressure of 60 psi). After the reaction was completed, the reaction solution was filtered through celite, neutralized with saturated sodium bicarbonate solution, and then stirred for 14 hours after an addition of 40 g of di-tert-butyl-dicarbonate. The reaction solution was evaporated under reduced pressure, and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate, 5:1(v/v)) to obtain 30.78 g of the desired compound (yield: 90%).

¹ H-NMR(CDCl₃, δ): 1.50(8H, s), 1.70˜2.00(2H, m), 2.20(1H, m), 2.50(1H, m), 2.80˜4.10(7H, m), 4.60(1H, m)

(5) Preparation of N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ene

17.1 g of N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ol and 7 ml of triethylamine were dissolved in 100 ml of methylene chloride. The reaction solution was cooled in an ice water bath, and then 4.2 ml of methanesulfonyl chloride was added dropwise thereto. The reaction mixture was stirred at room temperature for 10 hours, washed with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. The residue was dissolved in 50 ml of dimethylsulfoxide, and then 10 ml of DBU was added thereto. The reaction mixture was poured into 200 ml of ice water, extracted three times with ethyl acetate and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and subjected to a silica gel column chromatography (hexane:ethyl acetate, 6:1(v/v)) to obtain 9.8 g of the desired compound (yield: 61%).

¹ H-NMR(CDCl₃, δ): 1.46(18H, s), 2.10(1H, m), 2.70˜4.20(7H, m), 5.30(1H, m), 5.80(1H, m)

(6) Preparation of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrochloride

To 30 ml of methanol saturated with hydrogen chloride gas was added 9.72 g of N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ene, stirred at room temperature for 4 hours, and then evaporated under reduced pressure to obtain 5.85 g of the desired compound.

¹ H-NMR(CD₃ OD, δ): 2.10(1H, m), 2.70˜4.20(7H, m), 5.10(1H, m), 5.60(1H, m)

In vitro antibacterial activity test

In order to demonstrate the superior antibacterial activity of the quinolone derivatives of the present invention, the minimal inhibitory concentration (MIC, μg/ml) of several compounds synthesized in Examples hereof was determined in accordance with the agar culture medium two-fold dilution method (Hoechst 345) by using a Muller-Hinton agar medium. The strains having 10⁷ CFU/ml were inoculated on the culture medium, and the growth of the strains was observed after incubating them at 37° C. for 18 hours, in which ofloxacin, ciprofloxacin and spafloxacin were used as control materials. Hoechst standard strains were used as the test strains. The results of the MIC tests are shown in Tables 1 and 2.

                  TABLE 1                                                          ______________________________________                                         In vitro antibacterial activity test                                           Strain      A      B      C     D    E     F                                   ______________________________________                                         Streptococcus                                                                              0.391  0.195  0.781 3.125                                                                               3.125 1.363                               pyogenes 308A                                                                  Streptococcus                                                                              0.195  0.098  0.195 1.563                                                                               0.781 0.391                               pyogenes 77A                                                                   Streptococcus                                                                              0.195  0.195  0.195 0.781                                                                               0.781 0.391                               faecium MD 8b                                                                  Staphylococcus                                                                             0.025  0.013  0.025 0.391                                                                               0.391 0.049                               aureus SG 511                                                                  Staphylococcus                                                                             0.025  0.013  0.049 0.391                                                                               0.781 0.098                               aureus 285                                                                     Staphylococcus                                                                             0.025  0.013  0.013 0.391                                                                               0.781 0.025                               aureus 503                                                                     Escherichia coli                                                                           0.004  0.004  <0.002                                                                               0.013                                                                               <0.002                                                                               <0.002                              O 55                                                                           Escherichia coli                                                                           0.098  0.098  0.391 0.781                                                                               0.195 0.391                               DC 0                                                                           Escherichia coli                                                                           0.025  0.013  0.049 0.195                                                                               0.098 0.049                               DC 2                                                                           Escherichia coli                                                                           0.007  0.007  0.013 0.049                                                                               0.007 0.025                               TEM                                                                            Escherichia coli                                                                           0.013  0.013  0.013 0.049                                                                               0.007 0.025                               1507E                                                                          Pseudomonas 0.781  0.781  0.781 1.563                                                                               0.391 1.563                               aeruginosa 9027                                                                Pseudomonas 0.391  0.391  0.391 1.563                                                                               0.391 0.781                               aeruginosa 1592E                                                               Pseudomonas 0.391  0.391  0.391 1.563                                                                               0.391 0.781                               aeruginosa 1771                                                                Pseudomonas 0.195  0.195  0.195 0.391                                                                               0.098 0.195                               aeruginosa 1771M                                                               Salmonella  0.007  0.004  <0.002                                                                               0.049                                                                               0.007 0.013                               typhimurium                                                                    Klebsiella aerogenes                                                                       0.004  0.004  0.025 0.013                                                                               <0.002                                                                               <0.002                              1082E                                                                          Klebsiella aerogenes                                                                       0.013  0.013  0.007 0.098                                                                               0.007 0.049                               1552E                                                                          Enterobacter cloacas                                                                       0.007  0.007  <0.002                                                                               0.049                                                                               0.007 0.025                               P 99                                                                           Enterobacter cloacas                                                                       0.004  0.004  0.004 0.025                                                                               0.004 0.007                               1321E                                                                          ______________________________________                                          A: The compound prepared in Example 1                                          B: The compount prepared in Example 2                                          C: The compount prepared in Example 21                                         D: Ofloxacin                                                                   E: Ciprofloxacin                                                               F: Spafloxacin                                                           

                  TABLE 2                                                          ______________________________________                                         In vitro antibacterial activity against methicillin                            resistant Staphylococcus aureus                                                Strain           A       B       D     E                                       ______________________________________                                         Staphylococcus aureus 88E                                                                       0.049   0.195   0.391 0.781                                   Staphylococcus aureus 121 E                                                                     0.098   0.195   0.391 0.781                                   Staphylococcus aureus 208 E                                                                     0.098   0.195   0.391 0.781                                   Staphylococcus aureus 256 E                                                                     0.098   0.195   0.391 1.563                                   Staphylococcus aureus 690 E                                                                     0.049   0.098   0.391 0.781                                   Staphylococcus aureus 692 E                                                                     0.049   0.098   0.391 0.391                                   Staphylococcus aureus 693 E                                                                     0.049   0.098   0.391 0.781                                   Staphylococcus aureus 694 E                                                                     0.098   0.195   0.781 0.781                                   Staphylococcus aureus 695 E                                                                     0.049   0.098   0.391 0.781                                   Staphylococcus aureus 697 E                                                                     0.049   0.098   0.195 0.391                                   Staphylococcus aureus 701 E                                                                     0.098   0.195   0.391 0.781                                   Staphylococcus aureus 703 E                                                                     0.098   0.195   0.391 0.781                                   Staphylococcus aureus 705 E                                                                     0.098   0.195   0.391 0.781                                   Staphylococcus aureus 706 E                                                                     0.098   0.195   0.391 0.391                                   Staphylococcus aureus 707 E                                                                     0.098   0.195   0.391 0.781                                   Staphylococcus aureus 708 E                                                                     0.025   0.049   0.195 0.195                                   Staphylococcus aureus 711 E                                                                     0.025   0.098   0.391 0.781                                   Staphylococcus aureus 714 E                                                                     0.049   0.195   0.391 0.781                                   Staphylococcus aureus 725 E                                                                     0.098   0.195   0.391 0.781                                   ______________________________________                                          A: The compound prepared in Example 1                                          B: The compount prepared in Example 2                                          D: Ofloxacin                                                                   E: Ciprofloxacin                                                         

EXAMPLE 30 Preparation of (+)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride Step (1) Preparation of N,N'-di-(N-tosyl-L-prolyl)-2,8-diazabicyclo[4.3.0]non-5-ene

4.8 g of 2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride and 13.5 ml of triethylamine were added to 100 ml of chloroform and the reaction mixture was stirred for 5 min. 14.0 g of N-toxyl-L-prolyl chloride in 100 ml of chloroform was added to the reaction mixture under cold temperature (below 0° C.) and the resulting reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with 200 ml of chloroform, washed with 5% NaHCO₃ solution, next with 1N-HCl, and subsequently with NaCl solution, and dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate:methanol(v/v)=20:1) to obtain 6.6 g of more polar optical isomer of N,N'-di-(N-tosyl-L-prolyl)-2,8-diazabicyclo[4.3.0]non-5-ene and 5.79 g of less polar isomer of N,N'-di-(N-tosyl-L-prolyl)-2,8-diazabicyclo[4.3.0]non-5-ene.

more polar isomer: [α]²⁰ _(D) =-3.4° (c=1.0, CH₃ CH₂ OH)

¹ H-NMR(CDCl₃, δ): 1.7˜2.35(9H, m), 2.45(3H, s), 2.52(3H, s), 3.25˜3.60(6H, m), 3.52(1H, m), 3.29(1H, d), 4.13(1H, d), 4.33(1H, t), 4.40(1H, t), 4.60(2H, m), 5.95(2H, br, s), 7.30(4H, dxd), 7.72(4H, dxd)

less polar optical isomer: [α]²⁰ _(D) =-236.7° (c=1.0, CH₃ CH₂ OH

¹ H-NMR(CDCl₃, δ): 1.61(1H, m), 1.8˜2.2(9H, m), 2.30˜2.42(6H, dxd), 3.0˜3.55(6H, m), 3.9˜4.35(3H, m), 4.40˜5.0(4H, m), 6.0(1H, m), 7.30(4H, m), 7.75(4H, m)

Step (2) Preparation of (+)-N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ene

To 20 ml of ethanol and 100 ml of 8N-HCL solution was added 7.02 g of the more polar optical isomer of N,N'-di-(N-tosyl-L-prolyl)-2,8-diazabicyclo[4.3.0]non-5-ene and the reaction mixture was stirred for 3 hours under reflux. The resulting reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. To the residue were added 100 ml of methanol and 12.5 ml of triethylamine and the resulting mixture was stirred for 10 min. 9.8 g of di-t-butyldicarbonate was added to the reaction mixture and stirred for 10 hours at room temperature. The reaction solvent was evaporated under reduced pressure. The residue was dissolved in 100 ml of chloroform, washed with water, next with 5% acetic acid and subsequently with NaCl solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane (v/v=6:1) to obtain 3.0 g of desired compound (yield: 83%).

¹ H-NMR(CDCl₃. δ): 1.45(9H, s), 1.47(9H, s), 2.15(2H, m), 2.8˜2.9(2H, m), 3.9(3H, t), 4.05(1H, t), 4.3˜4.4(1H, m), 5.85(1H, br, s)

[α]²⁰ _(D) =+179° (c=1.0, MeOH)

Step (3) Preparation of (+)-2,8-diazabicyclo [4.3.0]non-5-ene dihydrogen chloride

3.02 g of (+)-N,N'-di-t-butoxycarbonyl-2,8-diazabicyclo[4.3.0]non-5-ene was dissolved in 18 ml of 8% HCl-methanol solution and stirred for 12 hours at room temperature. The solvent was evaporated under reduced pressure and the 5 ml of ethanol was added to the residue and stirred to give white solid product. The white solid was filtered, washed with mixed solution of ethanol and ethyl ether and dried under reduced pressure to give 1.26 g of desired white solid product (yield: 69%).

¹ H-NMR(CDCl₃, δ): 2.4(2H, m), 3.1˜3.3(2H, m), 3.5˜3.65(1H, m), 3.8˜4.1(3H, m), 4.2˜4.4(1H, m), 6.05(1H, br, s)

[α]²⁰ _(D) =+1.4° (c=27.2, H₂ O)

EXAMPLE 31 Preparation of (-)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride

7.2 g of the less polar optical isomer of N,N'-di-(N-tolsyl-L-prolyl)-2,8-diazabicyclo[4.3.0]non-5-ene was treated by the process described in Steps (2) and (3) of Example 30 to give 1.14 g of desired compound.

[α]²⁰ _(D) =-1.4° (c=27.2, H₂ O)

EXAMPLE 32 Preparation of 1-cyclopropyl-6-fluoro-7-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid

195 mg of (+)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride, 457 mg of DBU and 295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid were added to 2.5 ml of acetonitrile and stirred for 10 hours under reflux. The reaction mixture was cooled to room temperature to result in solid products. The resulting solid product was filtered, washed with 3 ml of acetonitrile and dried to give 312 mg of desired white solid product.

¹ H-NMR(CDCl₃, δ): 1.16(4H, m), 2.11(1H, m), 2.70˜4.20(7H, m), 4.02(3H, s), 4.65(1H, d), 5.70(1H, s), 7.84(1H, d), 8.80(1H, s)

EXAMPLE 33 Preparation of 1-cyclopropyl-6-fluoro-7-(((-)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl)-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid

195 mg of (-)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride was treated by the process described in Example 32 to give 296 mg of desired compound.

EXAMPLE 34 Preparation of 1-cyclopropyl-6-fluoro-7-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8 -yl)-8-chloro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid

195 mg of (+)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride and 299.5 mg of 1-cyclo-propyl-6,7-difluoro-8-chloro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid were treated by the process described in Example 32 to give 346 mg of desired compound.

¹ H-NMR(CDCl₃, δ){ 1.20(4H, m), 2.10(1H, m), 2.30(1H, m), 2.65˜4.10(7H, m), 4.93(1H, m), 5.10(1H, m), 5.63(1H, m), 7.56(1H, d), 8.61(1H, s)

EXAMPLE 35 Preparation of 1-cyclopropyl-5-amino-6,8-difluoro-7-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid

195 mg of (+)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride and 298 mg of 1-cyclo-propyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid were treated by the process described in Example 32 to give 298 mg of desired compound.

¹ H-NMR(CDCl₃, δ): 1.15(4H, m), 2.1(1H, m), 2.3(1H, m), 2.95(1H, m), 3.2˜4.0(6H, m), 4.65(1H, d), 5.75(1H, s), 8.90(1H, s)

EXAMPLE 36 Preparation of 9-fluoro-3-(S)-methyl-10-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-[1,4]-benzoxazin-6-carboxylic acid

200 mg of (+)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride and 280 mg of 9,10-difluoro-3-(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-[1,4]-benzoxazin-6-carboxylic acid were treated by the process described in Example 32 to give 250 mg of desired compound.

¹ H-NMR(CDCl₃, δ): 1.5()3H, d), 2.0(1H, m), 2.85(1H, m), 3.15(1H, m), 3.3˜3.6(4H, m), 3.7(1H, m), 3.9(2H, m), 4.2˜4.65(4H, m), 5.65(1H, br, s), 7.55(1H, d), 8.5(1H, s)

In vitro antibacterial activity test

The antibacterial activity of the compounds of the present invention was demonstrated in Table 3. The antibacterial activity was determined in accordance with the agar culture medium two-fold dilution method (Hoechst 345) by using a Muller-Hinton agar medium. Hoechst standard strains were used as the test strains. The strains having 10⁷ CFU/ml were inoculated on the culture medium, and the growth of the strains was observed after incubating them at 37° C. for 18 hours, in which ciprofloxacin was used as a control material.

                  TABLE 3                                                          ______________________________________                                         Strain/   Ex.     Ex.    Ex.   Ex.   Ex.  cipro-                               Substance 32      33     34    35    36   floxacin                             ______________________________________                                         Streptococcus                                                                            0.195   0.781  0.195 0.098 0.781                                                                               3.125                                pyogenes 308A                                                                  Streptococcus                                                                            0.098   0.391  0.098 0.098 0.195                                                                               0.781                                pyogenes 77A                                                                   Streptococcus                                                                            0.098   0.195  0.098 0.049 0.195                                                                               0.781                                faccium MD8b                                                                   Streptococcus                                                                            0.025   0.098  0.025 0.007 0.098                                                                               0.195                                aureus SG511                                                                   Streptococcus                                                                            0.025   0.098  0.025 0.013 0.195                                                                               0.391                                aureus 285                                                                     Streptococcus                                                                            0.013   0.049  0.025 0.004 0.098                                                                               0.781                                aureus 503                                                                     Escherichia                                                                              0.004   0.025  0.007 <0.002                                                                               0.025                                                                               <0.002                               coil O 78                                                                      Escherichia                                                                              0.195   1.563  0.195 0.098 0.391                                                                               0.195                                coil DC 0                                                                      Escherichia                                                                              0.025   0.098  0.025 0.025 0.098                                                                               0.098                                coil DC 2                                                                      Escherichia                                                                              0.013   0.049  0.013 <0.002                                                                               0.049                                                                               0.007                                coil TEM                                                                       Escherichia                                                                              0.013   0.098  0.013 0.004 0.049                                                                               0.007                                coil 1507E                                                                     Pseudomonas                                                                              1.563   3.125  0.781 0.781 0.781                                                                               0.391                                aeruginosa 9027                                                                Pseudomonas                                                                              0.781   1.563  0.391 0.391 0.391                                                                               0.195                                aeruginosa                                                                     1592E                                                                          Pseudomonas                                                                              0.781   1.563  0.391 0.391 0.781                                                                               0.195                                aeruginosa 1771                                                                Pseudomonas                                                                              0.195   0.781  0.195 0.098 0.195                                                                               0.049                                1771M                                                                          Salmonella                                                                               0.007   0.049  0.007 0.004 0.025                                                                               0.007                                typhimurium                                                                    Klebsiella                                                                               <0.002  0.007  <0.002                                                                               0.007 0.013                                                                               <0.002                               aerogenes 1082E                                                                Klebsiella                                                                               0.025   0.098  0.013 0.007 0.098                                                                               0.013                                aerogenes 1552E                                                                Enterobacter                                                                             0.004   0.025  0.007 <0.002                                                                               0.049                                                                               0.007                                cloacas P 99                                                                   Enterobacter                                                                             0.004   0.025  0.004 <0.002                                                                               0.025                                                                               <0.002                               cloacas 1321E                                                                  ______________________________________                                     

What is claimed is:
 1. A quinolone carboxylic acid derivative of formula (I): ##STR12## wherein, R₁, R₂, and R₃, which may be the same or different, are each hydrogen or a halogen atom, or a lower alkyl group optionally substituted with an amino or a hydroxy group;R₄ is a hydrogen atom, a lower alkyl, benzyl, t-butoxycarbonyl or ethoxycarbonyl group; R₅ is a hydrogen atom, a chlorine atom, a methyl group or an amino group; R₆ is a lower alkyl group, or a cyclopropyl group or a phenyl group optionally substituted with a halogen atom; and X is a nitrogen atom, and pharmaceutically acceptable salts thereof.
 2. The compound of claim 1 wherein the compound of formula (I) is selected from the group consisting of:1-cyclopropyl-6-fluoro-7-[2,8-diazabicyclo[4.3.0]non-5-en)8-yl]-4-oxo-1,8-naphthyridine-3-carboxylic acid; 1-(2,4-difluorophenyl)-6-fluoro-7-[2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-4-oxo-1,8naphthyridine-3-carboxylic acid; and 1-cyclopropyl-6-fluoro-7-[(2-methyl-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl]-1,8-dihydronaphthyridine-3-carboxylic acid.
 3. A pharmaceutical composition comprising a compound according to claim 1 as an active antibacterial ingredient in an effective amount.
 4. A method for the treatment of bacterial infection wherein a compound of claim 1 is administered to a host in need of such treatment in a therapeutically effective amount. 